1. Field of the Invention
The invention relates generally to substituted 2-aminotetralins and to processes for preparing such compounds. More particularly, the invention relates to compounds for therapeutic use, in particular in treating disorders of the central nervous, cardiovascular and endocrine systems. The compounds of this invention are also useful for alleviating glaucoma, parkinsonism, and schizophrenia, and for inducing anorexia and weight loss in mammals.
2. Background of the Prior Art
It is known that various hydroxylated 2-aminotetralins of the general formula ##STR3## where R.sub.1 and R.sub.2 are saturated alkyl groups and n is 1 or 2 are dopamine receptor agonists (McDermed et al., J. Med. Chem. 18, 362 (1975); Feenstra et al., Arch. Pharmacol. 313, 213 (1980).
Many structure-activity relationship studies have been conducted to find compounds with high dopamine-receptor stimulating activity. A survey is contained in Katerinopoulos, H. E., et al., "Structure-Activity Relationships for Dopamine Analogues," Druqs of the Future, Vol. 12, No. 3, 1987, 223-253. Based upon the high activity of apomorphine, many derivatives and simplified structural analogues have been tested and found to have dopaminergic activity. For instance, some of the bicyclic analogues of dopamine, 2-amino-5,6- and 2-amino-6,7-di-hydroxytetralin, and their N-alkylated derivatives were tested and showed activity.
In addition, studies have shown that the 5-hydroxy derivatives of 2-aminotetralins possess high potency almost equivalent to that of the 5,6 catechols, with the additional advantage of increased stability, selectivity and duration of biochemical action. These studies have also shown that in bicyclic compounds the size of the two nitrogen substituents controls activity. For instance, the N-butyl and N,N-dibutyl derivatives of 2-amino-5,6-dihydroxytetralin, dopamine and norapomorphine have little or no dopaminergic activity, while analogues having at least one N-ethyl or N-n-propyl group possess high activity.
Further studies have shown that the D.sub.2 receptor potency of dopamine agonists is at a maximum when one of the two N-substituents fits into a receptor niche which, because of size constraints, preferentially accommodates an n-propyl group. Conversely, activity drops off when the propyl group is replaced by the smaller groups ethyl or methyl. When the compound contains no N-substituent at least as small as n-propyl, activity is small or non-existent.
However, the structural requirements for the second N-substituent in such compounds have not been established. Consequently, the search continues for new and better N-substituents to enhance both dopamine receptor binding and activity, especially as shown by in vivo studies designed to test the dopaminergic activity of compounds, such as contralateral turning studies in 6-OH-DA-lesioned rats. See Seiler, Max P., et al., "Structure-Activity Relationships of Dopaminergic 5-Hydroxy-2-aminotetralin Derivatives with Functionalized N-Alkyl Substituents." J. Med. Chem. 1986, 29, 912-917.
The receptor site into which this second N-substituent is thought to interact appears to accommodate a wide variety of large, bulky groups having different functionalities without loss of activity. See McDermed, J. D., et al., J. Med. Chem. 1975. 18, 362; Cannon, J. G., et al., J. Med. Chem. 1977, 20, 1111; and Wikstroem, H., et al., J. Med. Chem. 1982 25, 925. However, the dopaminergic activity and potency conferred upon the compound by the choice of the second N-substituent is at present, unpredictable so that the search continues for new and better dopamine receptor agonists, especially for compounds showing a high degree of selectivity and specificity as either D.sub.1 or D.sub.2 receptor agonists.